Applying Principles of Developmental Biology to Generate Three-dimensional Lung Organoids from Human Pluripotent Stem Cells.

Abstract

The lungs are a complex organ consisting of two main anatomical features, the airways and alveoli. The airways form an arborized network of epithelial tubes surrounded by supporting tissue that conduct air in and out of the body. The airways connect to clusters of alveoli where gas exchange occurs between a thin epithelium and the surrounding vasculature. Any disruption to these tissues leads to the vast number of lung diseases that are known today. The number and severity of diseases affecting human lung development and adult respiratory function has stimulated great interest in deriving new in vitro models to study the human lung. Currently, a variety of animal models and cell culturing systems are used to model human lung development and adult homeostasis and disease. As described herein, I have taken two different approaches to understand how the lung develops normally. First, by utilizing mouse models, we have determined that a transcription factor, Sox9, which is expressed during lung development, is necessary to establish the proper arborized network of airways in the adult. Second, I used human pluripotent stem cells, which are grown in a tissue culture dish and are capable to differentiate into any cell type of the human body, in order to investigate human lung development and to derive a model for human lung disease. Using human pluripotent stem cells, we have developed a three-dimensional human lung model system that consists of structures that are similar to the human lung, including complex, multicellular lung epithelium and supporting tissue. This dissertation will describe my efforts to exploit both animal models and human cells grown in vitro in order to better understand how the lung develops into the complex airway and alveolar structures of the adult lung.PhDCell and Developmental BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/120888/1/rockichb_1.pd